Our work is aimed at understanding the control of apoptosis in terminally differentiated neurons. Specifically, we are investigating the mechanism of activation of apoptosis of Drosophila photoreceptor neurons (PRNs) in response to dominant point mutations of rhodopsin (Rh1). These point mutations cause autosomal dominant retinitis pigmentosa (ADRP) in people. In previous work, we determined that dim light sensitizes the retinas to the effects of the mutations and vice versa, and that lowered dosages of Hid, an RHG family protein, suppress both degeneration and loss of neuronal function in heterozygous Rh1 mutants. We have now found that lowered hid dosage suppresses degeneration and loss of visual function induced by light alone, as well as degeneration due to Rh1 mutations alone. Hid is thus an endogenous regulator of apoptosis in terminally differentiated neurons that acts downstream of light and mutant Rh1 pro-apoptotic signals. Further genetic studies have revealed additional candidates for the control of apoptosis in PRNs. We found that the role of the ras/MAPk signaling pathway in PRNs is paradoxically pro-apoptotic. This is in contrast to its role in developing PRNs, and we are further investigating this effect. We have also identified 3 strong suppressors and 1 strong enhancer of Rh1 mutant induced degeneration in novel areas of the genome. Future work will focus on identifying these modifier genes. In addition to these genetic studies, we are pursuing further development of the assays for degeneration and apoptosis in this system, as well as generating better tools for reverse genetics along with transgenic lines for assessing possible conditional mutant alleles. An important advance was made this year in understanding the basis of the apoptotic trigger provided by the Rh1 mutations. Earlier hypotheses based on less quantitative assays suggested that the ADRP mutations are toxic gain of function species or dominant negatives. However, we have found that the Rh1 mutations are actually hypomorphs (partial loss of function). These results reframe the central question from "How do the misfolded mutant proteins kill cells?" to "How does the wild type GPCR rhodopsin keep PRN cells alive?" Additinally, we discovered a neurotropic virus this year that was associated with a neurodegenerative phenotype. The only previously identified neurotropic virus in Drosophila is iota, which confers CO2 sensitivity on flies and is a member of a different family. The picorna-like virus we found by electron microscopy in retinas occurs in conjunction with apoptotic PRNs. The size, appearance and cytoplasmic localization of the virus particles suggested it to be a picorna-like virus. Infected stocks showed increased fertility and retinal degeneration that was reverted by hypochlorite disinfection of the embryos and rearing on fresh food. The reversion of phenotype by disinfection is consistent with the horizontal mode of transmission of the picorna-like viruses. We suspect the identity of this virus to be DCV, based on RT-PCR assays. While this discovery was an unintentional, it does provide the first evidence we know of for neurotropism of a picorna-like virus in Drosophila. Its occurrence and association with degeneration further suggests that an environmental factor that could contriburte to the wide variability of degenerative retinopathies may be viral infections. Moreover, it is a factor that must be controlled for in any studies of the neural system in flies. Based on the fact that virally associated degeneration was not suppressed by Hid, we suspect that experimental discrepancies between genetic results of different laboratories working on neurodegeneration in flies could be related to this endemic Drosophila virus.